Posaconazole is a derivative of itraconazole, and belongs to the second-generation triazole antifungal agents. It has the chemical name of 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one, and has the structural formula
U.S. Pat. No. 5,703,079 and U.S. Pat. No. 5,661,151, the disclosures of which in their entireties are hereby incorporated by reference into this application, disclose posaconazole and its synthetic method, respectively.
Posaconazole overcomes the problems of the first-generation triazole antifungal agents, i.e. narrow antibacterial spectrum, low bioavailability, drug resistance, etc., and has the characteristic of broad antibacterial spectrum. Posaconazole can prevent invasive aspergillosis more effectively by comparison with fluconazole and itraconazole, and can reduce the mortality rate in relation to invasive fungal infections.
A suspension containing posaconazole (40 mg/ml) in a crystalline form, Noxafil®, has been approved for the treatment of invasive fungal infections such as oropharyngeal candidiasis, including infections resistant to treatments with other azole antifungal agents, and for the prophylactic treatment of fungal infections in patients greatly susceptible to such infections due to severe immunodeficiency, such as hematopoietic stem cell transplantation (HSCT) receptors suffering from graft versus-host diseases (GVHD), or patients suffering from hematological malignances and having permanent leucopenia resulting from chemotherapy.
However, provision of pharmaceutical compositions comprising posaconazole suitable for the preparation of oral solid dosage forms has heretofore been hampered by the weak basicity and low solubility of posaconazole in free base form. Posaconazole has pKa values of 3.6 (piperazine) and 4.6 (triazole), and is slightly soluble at low pH. For example, in the environment of the stomach (pH=˜1.2), posaconazole in free base form has a solubility of about 0.8 mg/ml. However, when pH is higher than 4, posaconazole is practically insoluble (solubility <˜1 μg/ml). Therefore, when posaconazole dissolved in gastric fluid reaches the environment of the intestinal tract (typically, pH is or is higher than about 6.4) upon gastric emptying, the dissolved posaconazole crystallizes out, and thus the absorption of posaconazole is reduced and the bioavailability thereof is influenced.
US2011123627A discloses a posaconazole pharmaceutical composition comprising an enteric carrier material, the polymer hydroxypropylmethyl cellulose acetate succinate (HPMCAS), such that posaconazole is essentially insoluble when passing through stomach, but can be easily released upon entry into small intestine. This pharmaceutical composition improves the maximum plasma drug concentration and bioavailability of posaconazole in vivo by comparison with commercially available posaconazole oral suspensions. This pharmaceutical composition, however, limits the release of posaconazole in stomach, resulting in a delayed peak time (Tmax) of plasma drug concentration in vivo. In addition, a posaconazole pharmaceutical composition prepared by hot melt extrusion using HPMCAS as a carrier material has high hardness, leading to difficulties in grinding. Also, the pharmaceutical composition has poor compressibility, bringing difficulties in subsequent processing such as tableting.